Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression

Abstract

Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SHH pathway genes will be drug resistant. Thus, novel targeted therapies are needed. Here, we performed preclinical testing of the potent MEK inhibitor (MEKi) trametinib on tumor properties across 2 human and 3 mouse SHH MB models in vitro and in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduces tumorsphere size, stem/progenitor cell proliferation, viability, and migration. RNA-sequencing on human and mouse trametinib treated cells corroborated these findings with decreased expression of cell cycle, stem cell pathways and SHH-pathway related genes concomitant with increases in genes associated with cell death and ciliopathies. Importantly, trametinib also decreases tumor growth and increases survival in vivo. Cell cycle related E2F target gene sets are significantly enriched for genes that are commonly downregulated in both trametinib treated tumorspheres and primary xenografts. However, IL6/JAK STAT3 and TNFα/NFκB signaling gene sets are specifically upregulated following trametinib treatment in vivo indicative of compensatory molecular changes following long-term MEK inhibition. Our study reveals a novel role for trametinib in effectively attenuating SHH MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with other targeted therapies for the treatment of SHH MB exhibiting elevated MAPK pathway activity.

Overcoming Treatment Resistance in Medulloblastoma: Underlying Mechanisms and Potential Strategies

“…Additionally, BET inhibitors can also successfully suppress SMO signaling via GLI inhibition [ 113 ]. Trametinib, a MEK inhibitor, has shown encouraging results in primary studies targeting resistant SHH medulloblastoma [ 114 ]. In a parallel fashion, CK2 upregulation, associated with poor prognosis in various malignancies, has been assessed, and CX-4945 was identified as the first orally bioavailable selective CK2 inhibitor to be translated into clinical trials [ 115 , 116 , 117 ].…”